Allogeneic stem cell transplantation is an important treatment modality for AML. We and others have established that the benefit relates both to cytoreduction by the preparative regimen and the immune mediated graft-vs-leukemia (GVL) effect. Transplant results have improved over the last 3 decades, primarily related to improvements in supportive care. Unfortunately there has been little improvement in reducing the risk of leukemia relapse post transplant. The goal of this current proposal is to improve leukemia free survival by evaluation of novel approaches to improve the antileukemia cytoreduction by the preparative regimen and a novel strategy to reduce GVHD while retaining GVL. In the previous grant period, we demonstrated that the combination of intravenous busulfan and fludarabine is an effective preparative regimen for allogeneic stem cell transplantation with a low rate of treatment related mortality. This proposal seeks to further improve these results by optimizing the pharmacokinetics of busulfan (aim 1), combining the CXCR4 inhibitor AMD3100 with this regimen to provide synergistic antileukemia cytotoxicity (aim2) and favorably modulating GVHD and GVL effects with novel triterpenoids CDDO and CDDO-Me (aim 3). Specific Aims: Aim 1A) To optimize the antileukemia cytoreduction from the preparative regimen. We will test the hypothesis that administration of busulfan (Bu) given in a pharmacokinetically adjusted dose to yield a blood daily ADC of 6,000 uMol-min is superior to a fixed dose of 130 mg/m^ in this regimen to improve leukemia-free survival in patients with acute myelogenous leukemia and myelodysplastic syndrome. Correlative studies will examine pharmacogenetic predictors of response and resistance. 1B) A mechanistically based study will evaluate combination of clofarabine with busulfan and fludarabine with a goal of further improving leukemia-free survival. Aim 2) To test the hypothesis that the addition of AMD3100, a CXCR4 inhibitor, will improve the antileukemia effect of high dose busulfan-fludarabine with allogeneic stem cell transplantation for treatment of AML/MDS. Correlative studies will examine CXCR4 expression and related signaling on outcome. Aim 3) To test the hypothesis that post transplant treatment with CDDO and CDDO-Me will reduce GVHD while maintaining the antileukemia effect of allogeneic stem cell transplantation, thereby improving leukemia-free survival. This will be initially studied in a murine model (Aim 3A), with translation to a human clinical trial (Aim 3B).